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Process for the preparation of nebivolol

a synthesis process and nebivolol technology, applied in the field of new synthesis process of nebivolol, can solve problems such as the increase of the overall yield

Active Publication Date: 2013-11-07
MENARINI INT OPERATIN S LUXEMBORG SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a better way to make a drug called Nebivolol. The new process avoids the need for a step that separates out unwanted byproducts, and it also reduces the loss of product to other forms. The reaction is carried out in water and produces two compounds that can be easily separated. Overall, this new process makes it easier and more efficient to make Nebivolol.

Problems solved by technology

a) avoids, or considerably reduces, separation by preparative HPLC of the pairs (RR / SS RS / SR) of epoxides enantiomers or of other diastereoisomeric intermediates;
b) sensibly reduces the loss of product represented by undesired isomers, with a consequent increase of the overall yield.

Method used

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  • Process for the preparation of nebivolol
  • Process for the preparation of nebivolol
  • Process for the preparation of nebivolol

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0069]As described in EP-0687305, a strain of recombinant E. Coli containing the esterase originally expressed in Ophiostoma novo-ulmi is cultivated according to techniques well-known to a person skilled in the art. A cell fraction is lysed by sonication and the lysate centrifuged to obtain a cell-free supernatant solution. 1.6 mL of solution containing the esterase (lipase) enzyme obtained from Ophiostoma novo-ulmi (6800 units / mL) and a suspension of about 25 g of ethyl 6-fluorochroman-2-carboxylic acid (1) in 25 mL of deionized water with 100 μL of Tween 80, are added to 500 mL of a 0.1N NaHCO3 buffer solution (pH 9.7), optionally adjusting the pH with 2N NaOH to a value of 9.7. The mixture thus obtained is gently stirred.

[0070]pH is automatically maintained at the value of 9.7 with controlled additions of a 2N NaOH solution.

[0071]Evolution of the reaction is controlled by HPLC.

[0072]At the end of the hydrolysis reaction, the mixture is extracted with dichloromethane so as to obta...

example 2

Preparation of Acyl Meldrum Derivative

[0076]

[0077]28 g of resolved (R) acid are solubilized in 250 mL anhydrous dichloromethane; to the resulting solution, 1.4 equivalents of oxalyl chloride and DMF dropwise are added. The solution is maintained under stirring at room temperature and under N2; after 1.5 hours solvent is evaporated, obtaining an oil that is redissolved into 200 mL anhydrous dichloromethane. Separately, Meldrum's acid (1.05 equivalents) and pyridine (2 equivalents) are dissolved in anhydrous dichloromethane (150 mL) and left under stirring at 0° C. for 15 min. To this solution the previously formed acid chloride is added. At the end of the adding the mixture is left under stirring at 0° C. for 1 hour, and other 45 min at room temperature. Then, it is diluted with other 500 mL dichloromethane and the organic phase is washed with H2O (2×200 mL), 2N HCl (100 mL), water, and brine, and dried on Na2SO4. An oil is obtained which is taken up with 20 volumes of diisopropylete...

example 3

Preparation of β-Keto Ester

[0078]

[0079]40 grams of crude acyl Meldrum derivative (R) are placed under stirring with 110 mL tert-butanol; the resulting mixture is heated to 80° C. for 1 h until a control by HPLC highlights the disappearance of the starting product. At the end of the reaction, tert-butanol is evaporated under reduced pressure; it is taken up with 500 mL ethyl acetate and the organic phase is washed with a saturated NaHCO3 solution, H2O to neutrality, brine and it is dried on Na2SO4. Then the solvent is evaporated, obtaining 28 g of crude β-keto ester (HPLC purity=69%, λ=280 nm) as an oil, which is used in the subsequent reaction without further purification.

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Abstract

The present invention relates to a novel process for the synthesis of the Nebivolol product depicted in Scheme 1, comprised of a reduced number of high-yield steps, and characterized by the enzymatic resolution of the chroman ester precursor.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a novel process for the synthesis of Nebivolol.[0002]Nebivolol is a racemic mixture of the two enantiomers [2S[2R[R[R]]]]α,α′-[imino-bis(methylene)] bis[6-fluoro-chroman-2-methanol] and [2R[2S[S[S]]]]α,α′-[imino-bis(methylene)] bis[6-fluoro-chroman-2-methanol] (FIG. 1).[0003]In particular, it is reported the enzymatic resolution of the starting chromanyl ester (1) by treatment with a stereoselective enzyme belonging to the family of esterases, in a native or recombinant form, obtainable also from the microorganism Ophiostoma novo-ulmi. [0004]The esters and acids thus obtained can be converted, by processes known to a person skilled in the art, into the corresponding “semichiral” epoxides, i.e. the pairs (RR+RS, 4) and (SS+SR, 5) of Scheme (1).[0005]In turn, the components of each pair can be separated by exploiting their different reactivity with benzylamine in a solvent consisting of a tertiary alcohol. Under these condit...

Claims

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Application Information

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IPC IPC(8): C12P17/16
CPCC12P17/162C07D311/58C07D407/12
Inventor MAURO, SANDROFATTORI, DANIELACIPOLLONE, AMALIA
Owner MENARINI INT OPERATIN S LUXEMBORG SA
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